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Some behavioural effects of antidepressant drugs are time-dependent
Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 2001, Vol. 25, pp. 373-393 Copyright © 2001 Elsevaer Science Inc. Printed in the USA. All rights reserved 0278-5846/01/$--see front matter ELSEVIER
Pl/: 80278-5846(00~0169-x S O M E BEHAVIOURAL E F F E C T S OF ANTIDEPRF.~SANT DRUGS ARE TIME-DEPENDENT
MARTA DZIEDZICKA-WASYLEWSKA, ZOFIA ROGOZ, WOJCIECH MARGAS, DANIEL DLABOGA and MARTA GORALSKA Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland
(Final form, January 2001)
Abstract Dziedzicka-Wasylewska, Marta, Zofia Rog6~., Wojeiech Margas, Daniel Dlaboga and Marta G6ralska: Some Behavioural Effects of Antidepressant Drugs Are Time Dependent. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 2OOl,2fi, p p . 3 7 3 - - 3 9 3 . ¢~2001 E l s e v i e r S c i e n c e Inc.
I. The effects of repeated administration of antidepressant drugs (imipramine, IMI and citalopram, CIT) on the 13- and ~x2-adrenergicas well as dopaminergic D3 receptors were compared with time-dependent changes in the receptor responsiveness after acute treatment. 2. Repeated treatment with IMI or CIT (administered at a dose of 10 mg/kg p.o. twice a day for 14 days) induced down-regulation of I~-adrenergic receptors, demonstrated by behavioural experiment using salbutamol-induced hypoactivity and by binding studies using [3H]CGP12177. The changes in ¢x2adrenergic receptors were studied using clonidine-induced hypoactivity, which was attenuated by repeated treatment with IMI or CIT. Behavioural responsiveness of dopamine D3 receptors was investigated using two doses of 7-OH-DPAT. This drug at a dose of 0.05 mg/kg s.c. induced locomotor hypoactivity (interpreted as a result of stimulation of presynaptic dopamine D3 receptors), which was reversed by repeated administration of IMI or CIT, while 7-OH-DPAT at a dose of 3 mg/kg s.c. (which stimulated postsynaptic dopamine D3 receptors) induced significant hyperactivity, which was markedly enhanced by repeated administration of antidepressant drugs.
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3. The effect of acute administration of IMI or CIT measured 14 days after drug treatment were similar to the described above alterations at the level of cx2 adrenoreceptors and presynaptic dopamine D3 receptors, i.e. the drugs attenuated clonidine-induced hypoactivity and reversed locomotor hypoactivity evoked by low dose of 7-OH-DPAT. To induce the downregulation of 13-adrenergic receptors or up-regulation of the behavioural responsiveness of dopaminergic D3 postsynaptic receptors, the repeated administration of IMI or CIT was necessary. 4. Therefore it has been concluded that presynaptic dopaminergic D3 and ot2adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 and [5-adrenergic receptors. Keywords: antidepressant drugs, [3-adrenergic receptors, ot2-adrenergicreceptors, D3 dopaminergic receptors, time-dependent effects. Abbreviations: antidepressant drugs (ADs), citalopram (CIT), 7-hydroxydipropylaminotetralin (7-OH-DPAT), imipramine (IMI).
Introduction Succesful therapy with antidepressant drugs (ADs) requires repeated treatment. Therefore,
animal studies designed to define the changes, which may be
important for the mechanism of action of ADs, entail drug administration for at least two weeks. This research has been stimulated by the development of receptor binding techniques which enable rapid measures of the affinity and number of receptors for various neurotransmitters or neuromodulators involved in etiology and pharmacotherapy of affective disorders. Biochemical effects of ADs often correlate with the results of behavioural experiments designed to study particular receptor system. A decrease in a number of ~-adrenergic receptors in the rat brain after repeated treatment with ADs (the so-called 13-downregulation) was one of the first demonstrations of drug-induced alterations of biochemical receptor characteristics (Vetulani and Sulser, 1975). One of the behavioural experiments, which enable confirmation of this phenomenon involve testing drug
Time-dependent effects of antidepressant drugs
interference on hypoactivity induced by salbutamol (10 mg/kg), a [3-adrenergic receptor agonist. This effect is reversed by repeated treatment with ADs (Przegalinski et al., 1983), which correlates with the B-down regulation. Presynaptie ct2-adrenergic receptors control the release of noradrenaline from the central neurons (Langer 1981). The studies in rat indicate that chronic, but not acute, treatment with ADs results in the decreased sensitivity of ot2-adrenergic receptors to clonidine. Behavioural studies of the reactivity of c~2-adrenergic receptors are based on the clonidine (0.2 mg/kg s.c.)-induced hypoactivity, which is also reversed by repeated treatment with ADs (Spyraki and Fibiger, 1980). Another approach to the studies of the adaptive changes at the receptor level following repeated treatment with ADs consists in the use of dopaminergic agonists. Since the involvement of dopamine in the mechanism of action of antidepressant drugs was first suggested by Randrup et al. (1975), the supersensitivity of postsynaptic and subsensitivity of presynaptic dopaminergic D2 receptors was confirmed in numerous behavioural and biochemical studies (Dziedzicka-Wasylewska and Rog6~., 1997; Rogo~.and Dziedzieka-Wasylewska, 1999; Willner, 1997). Recently it has been shown (Maj et al., 1998) that ADs displaying different pharmacological profiles, administered repeatedly, increased the locomotor hyperactivity induced by a dose of 3 mg/kg of 7-hydroxydipropylaminotetralin (7-OH-DPAT) dopamine D3 receptor-preferring agonist (Damsma et al., 1993; L~vesque et al., 1992). The effect was interpreted as the supersensitivity of postsynaptic D3 receptors. On the other hand, low dose of 7OH-DPAT (0.05 mg/kg), most probably acting on presynaptic D3 receptors induced hypoactivity in rats, which was reversed by the repeated treatment with ADs (Rogoz and Dziedzicka-Wasylewska, submitted). Our recent studies investigated dopamine D2 receptor reactivity using behavioural tests (Dziedzicka-Wasylewska and Rog6z, 1997) and measured the
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level of mRNA encoding for dopamine D2 receptors in the rat brain (DziedzickaWasylewska, 1997). They have shown that at least some effects of ADs depend rather on time elapsing after last dose of the drug than on daily drug administration Therefore the present study was designed to find out whether a similar tendency could be observed on other receptor system, well-known to be susceptible to repeated treatment with ADs.
Methods
Animals The experiments were carried out on rats (male Wistar, 270-300g). The animals had free access to food and water before the experiment and were kept at a constant room temperature ( 22 + 1° C), under 12 hour light / dark cycle (light on at7 a.m.).
Drugs Imipramme hydrochloride (IMI, Polfa, Poland); citalopram hydrobromide (CIT, Lundbeck); salbutamol hydrochloride (Polfa Warszawa); clonidine hydrobromide (Research Biochemieals Int.); (+)-7-hydroxydipropyloaminotetralin hydrobomide (7-OH-DPAT; Research Biochemicals Int.),
Drug Administration IMI and CIT were dissolved in saline (0.9% NaC1) and administered perorally (p.o.) with a stomach tube at a dose of 10 mg/kg p.o., twice a day for 14 days (repeated treatment). Control groups received saline treatment (p.o.) while other groups of animals were treated acutely with IMI or CIT (2 x 10 mg/kg p.o.).
Time-dependent effects of antidepressant drugs
Acute treatment consisted in the administration of daily dose of antidepressant drug (20 mg/kg p.o.) followed by behavioural testing 2 (4 in case of 13-adrenergic receptors studies) or 72 hours, or 14 days thereafter. While not receiving the drug, all rats were treated with saline p.o. Respective control and experimental animals, treated acutely or repeatedly, were used for behavioural experiment or decapitated for biochemical experiments at the same time. Rat brain cortices for binding studies were quickly dissected, frozen and kept at -20°C until used. Each group consisted of 6-8 rats. Experimental protocols were approved by the Ethics Committee at the Institute of Pharmacology and meet the guidelines of the responsible governmental agency.
Salbutamol-Induced Exploratory Behaviour Salbutamol at a dose of 10 mg/kg i.p. was injected 2 hours after the last dose of IMI or CIT. Exploratory activity was investigated 2 hours after salbutamol injection, i.e. 4 hours after the last dose of the antidepressant. The test was performed in the open field without walls as described by Przegalifiski et al. (1983). Single animal was placed gently in the centre of the arena and allowed to explore freely. Ambulations (the number of crossings), rearings (the number of times an animal stood on its hind legs) and peepings (the number of times an animals peeped down from the edge of the arena) were recorded over 3 min by hand operated counters. Rearing and peeping reactions were pooled together because they are believed to represent the same kind of exploratory behaviour (Vetulani and Mogilnicka, 1970).
Clonidine-Induced Hypoactivity Clonidine dissolved in 0.9% NaCI solution, was given at a dose of 0.2 mg/kg s.c. 2 hours after the administration oflMI or CIT. Thirty and sixty minutes after
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clonidine injection the rats were placed in photoresistor actometers (with two crossed lightbeams) and a number of beam crossings was recorded for I hour.
7-OH-DPAT-Induced Locomotor Activity Locomotor activity was measured in photoresistor actometers (with two light beams), starting at 2 hours after single (acute experiment) or last (repeated experiment) administration oflMI or CIT. 7-OH-DPAT (0.05 or 3 mg/kg s.c.) was given at 2 hours after IMI or CIT administration. Locomotor activity measurements began 5 min after 7-OH-DPAT administration, and lasted for 2 hours.
Binding of [3H]CGP 12177 in Rat Cortical Membranes Brain cortices obtained from the appropriate groups of rats were homogenized for 30 s in 20 vol (w/v) of an ice-cold Tris-HCl buffer (50 raM, pH 7.4) . The homogenates were centrifuged at 25,000 g for 10 rain. That step was repeated twice. Final pellets were resuspended in 50 mM Tris-HC1 buffer (pH 7.4). Saturation isotherms were generated using eight concentrations (0.05 - 3 nM) of [3H]CGP 12177 (spec. activity 44.5 Ci/mmol). The non-specific binding was determined in the presence of 5 ~M propranolol. The data were analysed using iterative fitting routines (Graph PAD Prism 2.0).
Data Analyses The data were evaluated by one-way analysis of variance (ANOVA), followed, when appropriate, by individual comparisons with the control using Duncan's test (binding studies) or Dunnett's test (behavioural studies).
Time-dependent effects of antidepressant drugs
Results
Effect of IMI and CIT on fI-Adrenergic Receptors Salbutamol (10 mg/kg i.p.) induced hypoexploration in an open field test, manifested by the statistically significant decrease in time of walking, and a number of ambulations, and rearings + peepings. Both I/vii (Fig 1) and CIT (Fig 2) administered repeatedly significantly reversed the effect of salbutamol. The rats treated repeatedly with these antidepressants and challenged with salbutamol expressed the same exploratory activity as the control animals (Figs 1, 2). Groups of rats treated acutely with antidepressant drugs and tested 4, 72 hours or 14 days after IMI or CIT administration, did not show any differences in comparisons with the control in response to salbutamol challenge. However when IMI was given 14 days before the behavioural experiment, slight (approaching statistical significance) increase in the time of walking after injection of salbutamol was observed (Figs 1, 2). No such tendency was observed in the CIT treated group of rats. The studies of [3H]CGP12177 binding to fl-adrenergic receptors in the rat brain cortex showed the down-regulation of these receptors following repeated administration of IMI (significant decrease in Bmax). Again no alterations in the binding parameters of [3H]CGP12177 were observed in the groups of rats treated acutely with IMI, no matter whether studied at 4 or 72 hours, or 14 days after administration of the antidepressant (Fig 3). Since it has been shown by others that repeated administration of CIT does not induce the 13-adrenergic receptor down-regulation (Nalepa and Vetulani, 1993), we did not examine the [3H]CGP12177 binding following treatment with CIT.
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Effect of IMI and CIT on otz-Adrenergic Receptors Clonidine (0.2 mg/kg s.c.) induced locomotor hypoactivity which was reversed by the repeated treatment with IMI or CIT (Fig 4). Acute treatment with antidepressant drugs, which were given at 2 or 72 hours before the injection of clonidine, did not alter the clonidine-induced locomotor hypoactivity. However, in the groups of rats treated acutely with IMI or CIT 14 days before the behavioural experiment, the statistically significant (p<0.05) attenuation of clonidine-induced locomotor hypoactivity was observed (Fig 4).
Effect of IMI and CIT on Dopamine D3_Receptors The dose of 7-OH-DPAT (0.05 mg/kg), which is believed to act at the presynaptic D3 sites, induced strong statistically significant attenuation of the locomotor activity of the control animals receiving vehicle for 14 days. The effect of antidepressant drugs on the 7-OH-DPAT-induced locomotor hypoactivity is presented in Fig 5. Repeated treatment with IMI or CIT significantly reversed the sedative effect of 7-OH~DPAT (0.05 mg/kg). The same effect was observed in the groups of rats treated with IMI or CIT acutely 14 days before the behavioural experiment. However, acute treatment with IMI or CIT did not alter the 7-OHDPAT (0.05 mg/kg)-induced locomotor hypoactivity (Fig 5), when behavioural test was performed 2 or 72 hours after the drug administration The higher dose of 7-OH-DPAT (3 mg/kg) significantly increased the locomotor activity of rats (Fig 6). In this case,
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hyperactivity was further enhanced by repeated administration of IMI or CIT. Acute treatment with these antidepressant drugs did not modulate the locomotor hyperactivity induced by 7-OH-DPAT (3 mg/kg), regardless of time after acute treatment, i.e. 2 or 72 hours, or 14 days (Fig 6).
Time-dependent effects of antidepressant drugs
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Time-dependent effects of antidepressant drugs
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Time-dependent effects of antidepressant drugs
Discussion
Antidepressant drugs, IMI and CIT, used in the present study, given repeatedly evoke some well known effects, i.e. down-regulation of [3-adrenergic receptors, subsensitivity of tx2-adrenergic receptors to clonidine, subsensitivity of presynaptic dopaminergic D3 receptors and
supersensitivity of postsynaptic
dopaminergic D3 receptors, as differentiated by two doses of 7-OH-DPAT, the dopaminergic D3 receptor-preferring agonist (Damsma et al., 1993; L6vesque et al., 1992). Recently we have shown (Dziedzicka-Wasylewska, 1997; DziedzickaWasylewska and Rog6z, 1997) that some effects of antidepressant drugs administered repeatedly, such as the reversal of locomotor hypoactivity induced by low dose of apomorphine or the increase in the mRNA encoding dopaminergic D2 autoreceptors, were mimicked by the acute administration of these drugs provided that the drug effects were tested not earlier than 72 hours, but better after 14 days following the acute administration of antidepressant. There are also published data reporting the delayed effect of single administration of antidepressant drugs (Antelman et al., 1983; Lace and Antelman, 1983; Stewart and Rajabi, 1996). A very interesting work of Chiodo and Antelman (1980), was the first which showed that the attenuation of the ability of apomorphine to reduce the firing of the dopaminergic neurons in the zona compacta of substantia nigra induced by the repeated
antidepressant treatment depends on time elapsing after
drug administration rather than on the daily drug treatment. These findings might be explained if one takes into account the biochemical changes which receptor proteins undergo in the cell. It has already been discussed by others (Jongen-Relo et al., 1994; Mansour et al., 1990) that between the receptor synthesis and the availability of the functional receptors in the neuronal membrane, a complex series of events takes place, including post-transcriptional, translational and posttranslational processes, the subsequent incorporation of the receptor protein into
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cell membrane. Receptors (investigated in the present paper) perform their function by coupling through G proteins with the effector systems and eventually they undergo degradation. Although it has already been established that the halflife for dopamine D2 receptors is approximately 3-4 days (Qin et al., 1994), it may well be that acute treatment with antidepressant drugs is sufficient to trigger the cascade of events leading in consequence to the altered biosynthesis as well as functioning of dopamine D2 and, possibly D3, receptors. Other authors (Post, 1992; Duman et al., 1994) postulated that
the same mechanism might be
involved in stressor action and episode sensitization, which may leave residual traces and produce vulnerability to further occurrences of affective illness. It is well established that affective disorders evolve sequentially. They are triggered by stressful stimuli, which evoke stimulation of various neurotransmitter receptors, activation of second- and third-mesessenger systems, leading eventually to the long-lasting alterations in gene expression. Drugs used in the treatment of the central nervous system disorders are known or even designed to change the appropriate neurotransmission. Therefore, appropriate targeting, dosing and timing of the therapy is of critical importance. Such a conceptual scheme is even more justified in case of antidepressant drugs, which start to be clinically effective after at least two weeks of administration.
On the other hand however, such an effect of time elapsing after drug administration was not observed in the experiments with the higher dose of 7OH-DPAT (3 mg/kg), which is believed to stimulate postsynaptic dopamine D3 receptors. Only the repeated administration of antidepressant drugs was able to enhance the locomotor hyperactivity induced by this dose of 7-OH-DPAT. Similarly, in our previous studies, when D-amphetamine was used to stimulate locomotor activity, only repeated administration of various antidepressants
Time-dependent effects of antidepressant drugs
enhanced
D-amphetamine-induced
locomotor
hyperactivity
389
(Dziedzicka-
Wasylewska and Rogdz, 1997).
The results reported m the present studyalso indicate that down-regulation of 13adrenergic receptors is observed only in animals treated repeatedly with antidepressant drugs. In the light of the data published by Lace and Antelman (1983), indicating that 13-adrenergic receptor subsensitivity was observed when rats were treated with desmethylimipramine daily for 17 days or only on day 1 and day 17, one may suggest that the additional dose of antidepressant drug is necessary to evoke, biochemical or behavioural effects. This may indeed be true, especially if one considers this kind of experimental paradigm as a model for time-dependent sensitization, as Antelman et al. (1997), undoubtly do.
On the other hand, we have observed the effects of acute treatment with antidepressants on clonidine-induced hypoactivity only when IMI or CIT were given 14 days before the behavioural experiment. However, statistical significance was lower in this case (p<0.05 vs p<0.001).
Our experiments also indicate that only one dose of antidepressant administered 14 days before the behavioural experiment was needed to achieve the effect of acute treatment with IMI or CIT on presynaptic dopamine D3 receptors (and D2, as we have previously reported, Dziedzicka-Wasylewska and Rog6~., 1997) similar to the effect induced by repeated treatment, i.e. significant attenuation of locomotor hypoactivity induced by low dose of 7-OH-DPAT. We did not observe any correlation between this effect and biochemical receptor characteristics (data not shown). Only the repeated treatment with IMI or CIT induced the increase in the binding of [3H]7-OH-DPAT. However, this might result from the fact that we are not able to differentiate the presynaptic from postsynaptic population of D3
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receptors using dopamine D3 receptor autoradiography, and more specific technique would be necessary to resolve this issue.
Conclusion
The results presented in this paper indicate that presynaptic dopamine D3 and ct2-adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 or fl-adrenergic receptors. We still do not know, which of the known receptor changes often demonstrated in the studies of antidepressant drugs in experimental animals, even those confirmed in human studies, are the most important or even responsible for clinical efficacy of these drugs (Nestler, 1998; Healy and McMonagle, 1997). However, if the presynaptic dopaminergic or o~2-adrenergic receptors are the most crucial, one may speculate that there may be no need for repeated dally dosing schedules of these drugs, as suggested by Antelman et al. (1983, 1997), Antelman and Gershon (1998) and Lace and Antleman (1983) but instead comparable effects might be achieved if the drugs are given at weekly or biweekly interval.
Acknowledgment
This work was supported by Grant No 4P05A 007 13 from the State Committee for Scientific Research, Poland. The authors wish to thank H. Lundbeck for the generous gift of citalopram.
Time-dependent effects of antidepressant drugs
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JONGEN-RELO, A.R., DOCTER, G.J., JONKER, A.J., VRENGDENHIL, E., GROENWEGEN, H.J. and VOORN, P. (1994) Differential effects of dopamine depletion on the binding and mRNA levels of dopamine receptors in the shell and core of the rat nucleus accumbens. Mol. Brain Res. 25: 333-343. LACE, J.W. and ANTELMAN, S.M. (1983) Cortical 13-adrenergic subsensitivity after desmethylimipramine may depend on the passage of time rather than daily treatment. Brain Res. 278: 359-361. LANGER, S.Z. (1981) Presynaptic regulation of the release of catecholamines. Pharmacol. Rev. 32: 337-362. L~VESQUE, D., DIAZ, J., PILON, C., MARTRES, M.P., G/ROS, B., SOUIL, B., SCHOTT, D., MORGAT, J.L., SCHWARTZ, J.C. and SOKOLLOF, P. (1992) Identification, characterization and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-N-propyl-2-aminotetralin: Proc. Natl. Acad. Sci. U.S.A. 89: 8155-8159. MAJ, J., DZIEDZICKA-WASYLEWSKA, M., ROGOZ, R. and ROGOZ, Z. (1998) Effect of antidepressant drugs administered repeatedly on the dopamine D3 receptors in the rat brain. Eur. J. Pharmacol. 351: 31-37. MANSOUR, A., MEADOR-WOODRUFF, J.H., BUNZOW, J.R., CIVELLI, O., AKIL, H. and WATSON, S.J. (1990) Localization of dopamine D2 receptor mRNA and D~ and D2 receptor binding in the rat brain and pituitary: an in situ hybridization receptor autoradiography analysis. J. Neurosci. 10: 2587-2600. NALEPA, I. and VETULANI, J. (1993) Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5hydroxytryptamine uptake inhibitor citalopram. J. Neurochem. 60: 2029-2035. NESTLER, E.J. (1998) Antidepressant treatments in the 21 st century. Biol. Psychiatry 44: 526-533. POST, R.M. (1992) Transduction of psychosoeial stress into the neurobiology of recurrent affective disorder. Am. J. Psychiatry 149:999-1110. PRZEGALllqSKI, E., BARAN, L. and SIWANOWICZ, J. (1983) The effect of chronic treatment with antidepressant drugs on salbutamol-mduced hypoactivity in rats. Psychopharmacol. 80: 355-359.
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QIN, Z-H., CHEN, J.F. and WEISS, J. (1994) Lesions of mouse striatum induced by 6-hydroxydopamine differentially alter the density, rate of synthesis, and level of gene expression of D1 and D2 dopamine receptors. J. Neurochem. 6__22:411-420. RANDRUP, A., MUNKVAD, I., FOG, R., GERLACH, J., MOLANDER, L., KJELLBERG, B. and SCHEEL-KRUGER, J. (1975) Mania, depression and brain dopamme. In: Current developments in Psychopharmacology, W.B. Essman and V. Valzelli (Eds.), pp 206-248, Spectrum Publication, New York. ROGOZ, R. and DZIEDZICKA-WASYLEWSKA, M. (1999) Effects of antidepressant drugs on the dopamine D2/D3 receptors in the rat brain differentiated by agonist and antagonist binding - an autoradiographic analysis. Naunyn-Schmiedeberg's Arch. Pharmacol. 359: 178-186. SPYRAKI, C. and FIBIGER, H.C. (1980) Functional evidence for subsensitivity of noradrenergic ot2-receptors after chronic desipramine treatment. Life Sci. 27: 1863-1867. STEWART, J. and RAJABI, H. (1996) Initial increases in extracellular dopamine in the ventral tegmental area provide a mechanism for the development of desipramine-induced sensitization within the midbrain dopamine system. Synapse 23: 258-264. VETULANI, J. and MOGILNICKA, E. (1970) Neuroleptic action of metyloperone. Diss. Pharm. Phannacol. 2__22:105-116. VETULANI, J. and SULSER, F. (1975) Action of various antidepressant treatment reduces reactivity of noradrenergic cyclic AMP generating system in limbic forebrain. Nature 257: 495-496. WILLNER, P. (1997) The mesolimbic dopamine system as a target for rapid antidepressant action. Int. Clin. Psychopharmacol. 12: $7-S14.
Inquiries and reprint requests should be addressed to: Dr. Marta Dziedzicka-Wasylewska Institute of Pharmacology 12 Sm~tna Street 31-343 Krak6w, Poland
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Pl/: 80278-5846(00~0169-x S O M E BEHAVIOURAL E F F E C T S OF ANTIDEPRF.~SANT DRUGS ARE TIME-DEPENDENT
MARTA DZIEDZICKA-WASYLEWSKA, ZOFIA ROGOZ, WOJCIECH MARGAS, DANIEL DLABOGA and MARTA GORALSKA Institute of Pharmacology, Polish Academy of Sciences, Krak6w, Poland
(Final form, January 2001)
Abstract Dziedzicka-Wasylewska, Marta, Zofia Rog6~., Wojeiech Margas, Daniel Dlaboga and Marta G6ralska: Some Behavioural Effects of Antidepressant Drugs Are Time Dependent. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 2OOl,2fi, p p . 3 7 3 - - 3 9 3 . ¢~2001 E l s e v i e r S c i e n c e Inc.
I. The effects of repeated administration of antidepressant drugs (imipramine, IMI and citalopram, CIT) on the 13- and ~x2-adrenergicas well as dopaminergic D3 receptors were compared with time-dependent changes in the receptor responsiveness after acute treatment. 2. Repeated treatment with IMI or CIT (administered at a dose of 10 mg/kg p.o. twice a day for 14 days) induced down-regulation of I~-adrenergic receptors, demonstrated by behavioural experiment using salbutamol-induced hypoactivity and by binding studies using [3H]CGP12177. The changes in ¢x2adrenergic receptors were studied using clonidine-induced hypoactivity, which was attenuated by repeated treatment with IMI or CIT. Behavioural responsiveness of dopamine D3 receptors was investigated using two doses of 7-OH-DPAT. This drug at a dose of 0.05 mg/kg s.c. induced locomotor hypoactivity (interpreted as a result of stimulation of presynaptic dopamine D3 receptors), which was reversed by repeated administration of IMI or CIT, while 7-OH-DPAT at a dose of 3 mg/kg s.c. (which stimulated postsynaptic dopamine D3 receptors) induced significant hyperactivity, which was markedly enhanced by repeated administration of antidepressant drugs.
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3. The effect of acute administration of IMI or CIT measured 14 days after drug treatment were similar to the described above alterations at the level of cx2 adrenoreceptors and presynaptic dopamine D3 receptors, i.e. the drugs attenuated clonidine-induced hypoactivity and reversed locomotor hypoactivity evoked by low dose of 7-OH-DPAT. To induce the downregulation of 13-adrenergic receptors or up-regulation of the behavioural responsiveness of dopaminergic D3 postsynaptic receptors, the repeated administration of IMI or CIT was necessary. 4. Therefore it has been concluded that presynaptic dopaminergic D3 and ot2adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 and [5-adrenergic receptors. Keywords: antidepressant drugs, [3-adrenergic receptors, ot2-adrenergicreceptors, D3 dopaminergic receptors, time-dependent effects. Abbreviations: antidepressant drugs (ADs), citalopram (CIT), 7-hydroxydipropylaminotetralin (7-OH-DPAT), imipramine (IMI).
Introduction Succesful therapy with antidepressant drugs (ADs) requires repeated treatment. Therefore,
animal studies designed to define the changes, which may be
important for the mechanism of action of ADs, entail drug administration for at least two weeks. This research has been stimulated by the development of receptor binding techniques which enable rapid measures of the affinity and number of receptors for various neurotransmitters or neuromodulators involved in etiology and pharmacotherapy of affective disorders. Biochemical effects of ADs often correlate with the results of behavioural experiments designed to study particular receptor system. A decrease in a number of ~-adrenergic receptors in the rat brain after repeated treatment with ADs (the so-called 13-downregulation) was one of the first demonstrations of drug-induced alterations of biochemical receptor characteristics (Vetulani and Sulser, 1975). One of the behavioural experiments, which enable confirmation of this phenomenon involve testing drug
Time-dependent effects of antidepressant drugs
interference on hypoactivity induced by salbutamol (10 mg/kg), a [3-adrenergic receptor agonist. This effect is reversed by repeated treatment with ADs (Przegalinski et al., 1983), which correlates with the B-down regulation. Presynaptie ct2-adrenergic receptors control the release of noradrenaline from the central neurons (Langer 1981). The studies in rat indicate that chronic, but not acute, treatment with ADs results in the decreased sensitivity of ot2-adrenergic receptors to clonidine. Behavioural studies of the reactivity of c~2-adrenergic receptors are based on the clonidine (0.2 mg/kg s.c.)-induced hypoactivity, which is also reversed by repeated treatment with ADs (Spyraki and Fibiger, 1980). Another approach to the studies of the adaptive changes at the receptor level following repeated treatment with ADs consists in the use of dopaminergic agonists. Since the involvement of dopamine in the mechanism of action of antidepressant drugs was first suggested by Randrup et al. (1975), the supersensitivity of postsynaptic and subsensitivity of presynaptic dopaminergic D2 receptors was confirmed in numerous behavioural and biochemical studies (Dziedzicka-Wasylewska and Rog6~., 1997; Rogo~.and Dziedzieka-Wasylewska, 1999; Willner, 1997). Recently it has been shown (Maj et al., 1998) that ADs displaying different pharmacological profiles, administered repeatedly, increased the locomotor hyperactivity induced by a dose of 3 mg/kg of 7-hydroxydipropylaminotetralin (7-OH-DPAT) dopamine D3 receptor-preferring agonist (Damsma et al., 1993; L~vesque et al., 1992). The effect was interpreted as the supersensitivity of postsynaptic D3 receptors. On the other hand, low dose of 7OH-DPAT (0.05 mg/kg), most probably acting on presynaptic D3 receptors induced hypoactivity in rats, which was reversed by the repeated treatment with ADs (Rogoz and Dziedzicka-Wasylewska, submitted). Our recent studies investigated dopamine D2 receptor reactivity using behavioural tests (Dziedzicka-Wasylewska and Rog6z, 1997) and measured the
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level of mRNA encoding for dopamine D2 receptors in the rat brain (DziedzickaWasylewska, 1997). They have shown that at least some effects of ADs depend rather on time elapsing after last dose of the drug than on daily drug administration Therefore the present study was designed to find out whether a similar tendency could be observed on other receptor system, well-known to be susceptible to repeated treatment with ADs.
Methods
Animals The experiments were carried out on rats (male Wistar, 270-300g). The animals had free access to food and water before the experiment and were kept at a constant room temperature ( 22 + 1° C), under 12 hour light / dark cycle (light on at7 a.m.).
Drugs Imipramme hydrochloride (IMI, Polfa, Poland); citalopram hydrobromide (CIT, Lundbeck); salbutamol hydrochloride (Polfa Warszawa); clonidine hydrobromide (Research Biochemieals Int.); (+)-7-hydroxydipropyloaminotetralin hydrobomide (7-OH-DPAT; Research Biochemicals Int.),
Drug Administration IMI and CIT were dissolved in saline (0.9% NaC1) and administered perorally (p.o.) with a stomach tube at a dose of 10 mg/kg p.o., twice a day for 14 days (repeated treatment). Control groups received saline treatment (p.o.) while other groups of animals were treated acutely with IMI or CIT (2 x 10 mg/kg p.o.).
Time-dependent effects of antidepressant drugs
Acute treatment consisted in the administration of daily dose of antidepressant drug (20 mg/kg p.o.) followed by behavioural testing 2 (4 in case of 13-adrenergic receptors studies) or 72 hours, or 14 days thereafter. While not receiving the drug, all rats were treated with saline p.o. Respective control and experimental animals, treated acutely or repeatedly, were used for behavioural experiment or decapitated for biochemical experiments at the same time. Rat brain cortices for binding studies were quickly dissected, frozen and kept at -20°C until used. Each group consisted of 6-8 rats. Experimental protocols were approved by the Ethics Committee at the Institute of Pharmacology and meet the guidelines of the responsible governmental agency.
Salbutamol-Induced Exploratory Behaviour Salbutamol at a dose of 10 mg/kg i.p. was injected 2 hours after the last dose of IMI or CIT. Exploratory activity was investigated 2 hours after salbutamol injection, i.e. 4 hours after the last dose of the antidepressant. The test was performed in the open field without walls as described by Przegalifiski et al. (1983). Single animal was placed gently in the centre of the arena and allowed to explore freely. Ambulations (the number of crossings), rearings (the number of times an animal stood on its hind legs) and peepings (the number of times an animals peeped down from the edge of the arena) were recorded over 3 min by hand operated counters. Rearing and peeping reactions were pooled together because they are believed to represent the same kind of exploratory behaviour (Vetulani and Mogilnicka, 1970).
Clonidine-Induced Hypoactivity Clonidine dissolved in 0.9% NaCI solution, was given at a dose of 0.2 mg/kg s.c. 2 hours after the administration oflMI or CIT. Thirty and sixty minutes after
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clonidine injection the rats were placed in photoresistor actometers (with two crossed lightbeams) and a number of beam crossings was recorded for I hour.
7-OH-DPAT-Induced Locomotor Activity Locomotor activity was measured in photoresistor actometers (with two light beams), starting at 2 hours after single (acute experiment) or last (repeated experiment) administration oflMI or CIT. 7-OH-DPAT (0.05 or 3 mg/kg s.c.) was given at 2 hours after IMI or CIT administration. Locomotor activity measurements began 5 min after 7-OH-DPAT administration, and lasted for 2 hours.
Binding of [3H]CGP 12177 in Rat Cortical Membranes Brain cortices obtained from the appropriate groups of rats were homogenized for 30 s in 20 vol (w/v) of an ice-cold Tris-HCl buffer (50 raM, pH 7.4) . The homogenates were centrifuged at 25,000 g for 10 rain. That step was repeated twice. Final pellets were resuspended in 50 mM Tris-HC1 buffer (pH 7.4). Saturation isotherms were generated using eight concentrations (0.05 - 3 nM) of [3H]CGP 12177 (spec. activity 44.5 Ci/mmol). The non-specific binding was determined in the presence of 5 ~M propranolol. The data were analysed using iterative fitting routines (Graph PAD Prism 2.0).
Data Analyses The data were evaluated by one-way analysis of variance (ANOVA), followed, when appropriate, by individual comparisons with the control using Duncan's test (binding studies) or Dunnett's test (behavioural studies).
Time-dependent effects of antidepressant drugs
Results
Effect of IMI and CIT on fI-Adrenergic Receptors Salbutamol (10 mg/kg i.p.) induced hypoexploration in an open field test, manifested by the statistically significant decrease in time of walking, and a number of ambulations, and rearings + peepings. Both I/vii (Fig 1) and CIT (Fig 2) administered repeatedly significantly reversed the effect of salbutamol. The rats treated repeatedly with these antidepressants and challenged with salbutamol expressed the same exploratory activity as the control animals (Figs 1, 2). Groups of rats treated acutely with antidepressant drugs and tested 4, 72 hours or 14 days after IMI or CIT administration, did not show any differences in comparisons with the control in response to salbutamol challenge. However when IMI was given 14 days before the behavioural experiment, slight (approaching statistical significance) increase in the time of walking after injection of salbutamol was observed (Figs 1, 2). No such tendency was observed in the CIT treated group of rats. The studies of [3H]CGP12177 binding to fl-adrenergic receptors in the rat brain cortex showed the down-regulation of these receptors following repeated administration of IMI (significant decrease in Bmax). Again no alterations in the binding parameters of [3H]CGP12177 were observed in the groups of rats treated acutely with IMI, no matter whether studied at 4 or 72 hours, or 14 days after administration of the antidepressant (Fig 3). Since it has been shown by others that repeated administration of CIT does not induce the 13-adrenergic receptor down-regulation (Nalepa and Vetulani, 1993), we did not examine the [3H]CGP12177 binding following treatment with CIT.
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Effect of IMI and CIT on otz-Adrenergic Receptors Clonidine (0.2 mg/kg s.c.) induced locomotor hypoactivity which was reversed by the repeated treatment with IMI or CIT (Fig 4). Acute treatment with antidepressant drugs, which were given at 2 or 72 hours before the injection of clonidine, did not alter the clonidine-induced locomotor hypoactivity. However, in the groups of rats treated acutely with IMI or CIT 14 days before the behavioural experiment, the statistically significant (p<0.05) attenuation of clonidine-induced locomotor hypoactivity was observed (Fig 4).
Effect of IMI and CIT on Dopamine D3_Receptors The dose of 7-OH-DPAT (0.05 mg/kg), which is believed to act at the presynaptic D3 sites, induced strong statistically significant attenuation of the locomotor activity of the control animals receiving vehicle for 14 days. The effect of antidepressant drugs on the 7-OH-DPAT-induced locomotor hypoactivity is presented in Fig 5. Repeated treatment with IMI or CIT significantly reversed the sedative effect of 7-OH~DPAT (0.05 mg/kg). The same effect was observed in the groups of rats treated with IMI or CIT acutely 14 days before the behavioural experiment. However, acute treatment with IMI or CIT did not alter the 7-OHDPAT (0.05 mg/kg)-induced locomotor hypoactivity (Fig 5), when behavioural test was performed 2 or 72 hours after the drug administration The higher dose of 7-OH-DPAT (3 mg/kg) significantly increased the locomotor activity of rats (Fig 6). In this case,
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hyperactivity was further enhanced by repeated administration of IMI or CIT. Acute treatment with these antidepressant drugs did not modulate the locomotor hyperactivity induced by 7-OH-DPAT (3 mg/kg), regardless of time after acute treatment, i.e. 2 or 72 hours, or 14 days (Fig 6).
Time-dependent effects of antidepressant drugs
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Time-dependent effects of antidepressant drugs
Discussion
Antidepressant drugs, IMI and CIT, used in the present study, given repeatedly evoke some well known effects, i.e. down-regulation of [3-adrenergic receptors, subsensitivity of tx2-adrenergic receptors to clonidine, subsensitivity of presynaptic dopaminergic D3 receptors and
supersensitivity of postsynaptic
dopaminergic D3 receptors, as differentiated by two doses of 7-OH-DPAT, the dopaminergic D3 receptor-preferring agonist (Damsma et al., 1993; L6vesque et al., 1992). Recently we have shown (Dziedzicka-Wasylewska, 1997; DziedzickaWasylewska and Rog6z, 1997) that some effects of antidepressant drugs administered repeatedly, such as the reversal of locomotor hypoactivity induced by low dose of apomorphine or the increase in the mRNA encoding dopaminergic D2 autoreceptors, were mimicked by the acute administration of these drugs provided that the drug effects were tested not earlier than 72 hours, but better after 14 days following the acute administration of antidepressant. There are also published data reporting the delayed effect of single administration of antidepressant drugs (Antelman et al., 1983; Lace and Antelman, 1983; Stewart and Rajabi, 1996). A very interesting work of Chiodo and Antelman (1980), was the first which showed that the attenuation of the ability of apomorphine to reduce the firing of the dopaminergic neurons in the zona compacta of substantia nigra induced by the repeated
antidepressant treatment depends on time elapsing after
drug administration rather than on the daily drug treatment. These findings might be explained if one takes into account the biochemical changes which receptor proteins undergo in the cell. It has already been discussed by others (Jongen-Relo et al., 1994; Mansour et al., 1990) that between the receptor synthesis and the availability of the functional receptors in the neuronal membrane, a complex series of events takes place, including post-transcriptional, translational and posttranslational processes, the subsequent incorporation of the receptor protein into
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cell membrane. Receptors (investigated in the present paper) perform their function by coupling through G proteins with the effector systems and eventually they undergo degradation. Although it has already been established that the halflife for dopamine D2 receptors is approximately 3-4 days (Qin et al., 1994), it may well be that acute treatment with antidepressant drugs is sufficient to trigger the cascade of events leading in consequence to the altered biosynthesis as well as functioning of dopamine D2 and, possibly D3, receptors. Other authors (Post, 1992; Duman et al., 1994) postulated that
the same mechanism might be
involved in stressor action and episode sensitization, which may leave residual traces and produce vulnerability to further occurrences of affective illness. It is well established that affective disorders evolve sequentially. They are triggered by stressful stimuli, which evoke stimulation of various neurotransmitter receptors, activation of second- and third-mesessenger systems, leading eventually to the long-lasting alterations in gene expression. Drugs used in the treatment of the central nervous system disorders are known or even designed to change the appropriate neurotransmission. Therefore, appropriate targeting, dosing and timing of the therapy is of critical importance. Such a conceptual scheme is even more justified in case of antidepressant drugs, which start to be clinically effective after at least two weeks of administration.
On the other hand however, such an effect of time elapsing after drug administration was not observed in the experiments with the higher dose of 7OH-DPAT (3 mg/kg), which is believed to stimulate postsynaptic dopamine D3 receptors. Only the repeated administration of antidepressant drugs was able to enhance the locomotor hyperactivity induced by this dose of 7-OH-DPAT. Similarly, in our previous studies, when D-amphetamine was used to stimulate locomotor activity, only repeated administration of various antidepressants
Time-dependent effects of antidepressant drugs
enhanced
D-amphetamine-induced
locomotor
hyperactivity
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(Dziedzicka-
Wasylewska and Rogdz, 1997).
The results reported m the present studyalso indicate that down-regulation of 13adrenergic receptors is observed only in animals treated repeatedly with antidepressant drugs. In the light of the data published by Lace and Antelman (1983), indicating that 13-adrenergic receptor subsensitivity was observed when rats were treated with desmethylimipramine daily for 17 days or only on day 1 and day 17, one may suggest that the additional dose of antidepressant drug is necessary to evoke, biochemical or behavioural effects. This may indeed be true, especially if one considers this kind of experimental paradigm as a model for time-dependent sensitization, as Antelman et al. (1997), undoubtly do.
On the other hand, we have observed the effects of acute treatment with antidepressants on clonidine-induced hypoactivity only when IMI or CIT were given 14 days before the behavioural experiment. However, statistical significance was lower in this case (p<0.05 vs p<0.001).
Our experiments also indicate that only one dose of antidepressant administered 14 days before the behavioural experiment was needed to achieve the effect of acute treatment with IMI or CIT on presynaptic dopamine D3 receptors (and D2, as we have previously reported, Dziedzicka-Wasylewska and Rog6~., 1997) similar to the effect induced by repeated treatment, i.e. significant attenuation of locomotor hypoactivity induced by low dose of 7-OH-DPAT. We did not observe any correlation between this effect and biochemical receptor characteristics (data not shown). Only the repeated treatment with IMI or CIT induced the increase in the binding of [3H]7-OH-DPAT. However, this might result from the fact that we are not able to differentiate the presynaptic from postsynaptic population of D3
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receptors using dopamine D3 receptor autoradiography, and more specific technique would be necessary to resolve this issue.
Conclusion
The results presented in this paper indicate that presynaptic dopamine D3 and ct2-adrenergic receptors are more sensitive to the acute treatment with antidepressant drugs than postsynaptic D3 or fl-adrenergic receptors. We still do not know, which of the known receptor changes often demonstrated in the studies of antidepressant drugs in experimental animals, even those confirmed in human studies, are the most important or even responsible for clinical efficacy of these drugs (Nestler, 1998; Healy and McMonagle, 1997). However, if the presynaptic dopaminergic or o~2-adrenergic receptors are the most crucial, one may speculate that there may be no need for repeated dally dosing schedules of these drugs, as suggested by Antelman et al. (1983, 1997), Antelman and Gershon (1998) and Lace and Antleman (1983) but instead comparable effects might be achieved if the drugs are given at weekly or biweekly interval.
Acknowledgment
This work was supported by Grant No 4P05A 007 13 from the State Committee for Scientific Research, Poland. The authors wish to thank H. Lundbeck for the generous gift of citalopram.
Time-dependent effects of antidepressant drugs
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Inquiries and reprint requests should be addressed to: Dr. Marta Dziedzicka-Wasylewska Institute of Pharmacology 12 Sm~tna Street 31-343 Krak6w, Poland
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